1. Field of the Invention
The invention relates to genomic clones encoding histamine receptors, recombinant histamine receptors, and methods for producing said genomic clones.
2. Discussion of the Background
Histamine is one of the major determinants of gastric acid secretion. Through its three known receptor subclasses (H1, H2 and H3), histamine has been shown to exert a broad array of physiological activity, including mediation of allergic and anaphylactic responses (H1), modulation of cardiac contractility and systemic blood pressure (H1 and H2), and mediation of neural function in the central nervous system (H3).
Perhaps the best known activity of histamine involves its relationship to gastric acid secretion (H2 only). Antagonism of the histamine ligand at the H2 receptor has been the cornerstone of a current $3 billion market for pharmacological treatment of acid-peptic disorders of the gastrointestinal tract. The need, and potential market for the histamine H2 receptor clone is enormous because this receptor is presumed to be the primary mediator of gastric acid secretion. However despite a wealth of pharmacological information, little else is known about the structure of the histamine receptors.
H1 receptors are the mediators of many allergic reactions such as are caused by hay fever and antihistamines are in widespread use for treatment of symptoms resulting from allergies. Currently there are few, if any, histamine H1 selective antagonists and it is thought that availability of a gene encoding this receptor will greatly facilitate the development of compounds useful for the treatment of common allergies.
The function of the histamine H3 receptor subclass is currently unknown, except that it is present in the brain and its function may be related to general neural activity and possible cognitive function. The availability of a recombinant clone encoding the histamine H3 receptor gene obtained with the use of the histamine H2 receptor gene as a probe would permit the discovery of the function of the H3 receptor more thoroughly and possibly lead to therapeutically useful neuroactive compounds.
Currently there is no structural information on any of the subclasses of the histamine receptor. It is known that each subclass of histamine receptor is concentrated in a different type of cell. Pharmacological behavior corresponding to the H1 subclass is readily displayed in, e.g., smooth muscle and capillary cells, whereas the H2 subclass is associated with stomach cells, notably gastric parietal cells, and the H3 subclass is associated with neural cells.
There is an ongoing search to develop better and more effective histamine antagonists. The availability of the histamine H2 receptor gene will facilitate the development of such compounds. Moreover, the gene encoding this receptor, once obtained, can be utilized to isolate the also much needed genes encoding the two other major subclasses of histamine receptors (H1 and H3).